Thienodiazepine derivatives as cholecystokinin and gastrin antagonists

ABSTRACT

Thienodiazepine compounds of formula (1) wherein: R 1  represents H, optionally substituted C 1-6  alkyl or C 3-7  cycloalkyl; R 2  represents optionally substituted phenyl; or R 2  represents a group (a) where W is CH 2  or NR 9  and W 1  is CH 2  or W and W 1  are each O; R 3  is C 3-7  cycloalkyl optionally substituted by one or more C 1-4  alkyl groups, or R 3  is NR 11  R 12 , where R 11  and R 12  are each H; C 1-12  alkyl optionally substituted by NR 9  R 9  or an azacyclic or azabicyclic group; C 4-9  cycloalkyl optionally substituted by one or more C 1-4  alkyl groups; C 4-9  cycloalkylC 1-4  alkyl optionally substituted in the cycloalkyl ring by one or more C 1-4  alkyl groups; optionally substituted aryl; optionally substituted arylC 1-6  alkyl; or azacyclic or azabicyclic groups; or R 11  and R 12  together form the residue of an optionally substituted azacylcic or azabicyclic ring system; and salts or prodrugs thereof are CCK and/or gastrin receptor antagonists useful in therapy.

This invention relates to thienodiazepine compounds which are useful asantagonists of cholecystokinin and gastrin receptors.

Cholecystokinins (CCK) and gastrin are structurally related peptideswhich exist in gastrointestinal tissue and in the central nervous system(see, V. Mutt, Gastrointestinal Hormones, G. B. J. Green, Ed., RavenPress, N.Y., p.169 and G. Nission, ibid. p.127).

Cholecystokinins include CCK-33, a neuropeptide of thirty-three aminoacids in its originally isolated form (see, Mutt and Jorpes, Biochem. J.125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (also anaturally-occurring neuropeptide and the minimum fully active sequence),and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-aminoacid forms, with the minimum active sequence being the C-terminaltetrapeptide, Trp-Met-Asp-Phe-NH2, which is the common structuralelement shared by both CCK and gastrin.

CCKs are believed to be physiological satiety hormones, thereby possiblyplaying an important role in appetite regulation (G. P. Smith, Eatingand Its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven Press, NewYork, 1984, p. 67), as well as stimulating colonic motility, gallbladder contraction, pancreatic enzyme secretion and inhibiting gastricemptying. They reportedly co-exist with dopamine in certain mid-brainneurons and thus may also play a role in the functioning of dopaminergicsystems in the brain, in addition to serving as neurotransmitters intheir own right (see A. J. Prange et al., "Peptides in the CentralNervous System", Ann. Repts. Med. Chem 17, 31, 33 [1982] and referencescited therein; J. A. Williams, Biomed Res. 3 107 [1982]; and J. E.Morley, Life Sci. 30, 479 [1982]).

The primary role of gastrin, on the other hand, appears to bestimulation of the secretion of water and electrolytes from the stomachand, as such, is involved in control of gastric acid and pepsinsecretion. Other physiological effects of gastrin then include increasedmucosal blood flow and increased antral motility. Rat studies have shownthat gastrin has a positive trophic effect on the gastric mucosa, asevidenced by increased DNA, RNA and protein synthesis.

There are at least two subtypes of cholecystokinin receptors termedCCK-A and CCK-B (T. H. Moran et al., "Two brain cholecystokininreceptors: implications for behavioural actions" Brain Res , 362, 175-79[1986]). Both subtypes are found both in the periphery and in thecentral nervous system.

CCK and gastrin receptor antagonists have been disclosed for preventingand treating CCK-related and/or gastrin related disorders of thegastrointestinal (GI) and central nervous (CNS) systems of animals,especially mammals, and more especially those of humans. Just as thereis some overlap in the biological activities of CCK and gastrin,antagonists also tend to have affinity for both CCK-B receptors andgastrin receptors. Other antagonists have activity at the CCK-A subtype.

Selective CCK antagonists are themselves useful in treating CCK-relateddisorders of appetite regulatory systems of animals as well as inpotentiating and prolonging opiate-mediated analgesia [see P. L. Fariset al., Science 226, 1215 (1984)], thus having utility in the treatmentof pain. CCK-B and CCK-A antagonists have also been shown to have adirect analgesic effect [M. F. O'Neill et al., Brain Research, 534 287(1990)]. Selective CCK and gastrin antagonists are useful in themodulation of behaviour mediated by dopaminergic and serotonergicneuronal systems and thus have utility in the treatment of schizophreniaand depression (Rasmussen et. al., 1991, Eur. J. Pharmacol., 209,135-138; Woodruff et. al., 1991, Neuropeptides, 19, 45-46; Cervo et.al., 1988, Eur. J. Pharmacol., 158, 53-59), as a palliative forgastrointestinal neoplasms, and in the treatment and prevention ofgastrin-related disorders of the gastrointestinal system in humans andanimals, such as peptic ulcers, Zollinger-Ellison syndrome, antral Gcell hyperplasia and other conditions in which reduced gastrin activityis of therapeutic value, see e.g. U.S. Pat. No. 4,820,834. Certain CCKantagonists are useful anxiolytic agents and can be used in thetreatment of panic and anxiety disorders.

CCK has been reported to evoke the release of stress hormones such asadrenocorticotrophic hormone, β-endorphin, vasopressin and oxytocin, CCKmay function as a mediator of responses to stress and as part of thearousal system. CCK-A receptors are now known to be present in a numberof areas of the CNS and may be involved in modulating all of the above.

CCK may be involved in the regulation of stress and its relationshipwith drug abuse e.g. alleviation of the benzodiazepine withdrawalsyndrome (Singh et. al., 1992, Br. J. Pharmacol., 105, 8-10) andneuroadaptive processes.

Since CCK and gastrin also have trophic effects on certain tumours [K.Okyama, Hokkaido J. Med. Sci., 206-216 (1985)], antagonists of CCK andgastrin are useful in treating these tumours [see, R. D. Beauchamp etal., Ann. Surg., 202, 203 (1985)].

In the light of discussion in C. Xu et al., Peptides, 8, 1987, 769-772,CCK antagonists may also be effective in neuroprotection.

CCK receptor antagonists have been found to inhibit the contractileeffects of CCK on iris sphincter and ciliary muscles of monkey and humaneyes (Eur. J. Pharmacol., 211(2), 183-187; A. Bill et al., Acta Physiol.Scand., 138, 479-485 [1990]), thus having utility in inducing miosis fortherapeutic purposes.

A class of benzodiazepine antagonist compounds has been reported whichbinds selectively to brain CCK (CCK-B and CCK-A) and gastrin receptors[see M. Bock et al., J. Med Chem., 32, 13-16 (1989)].

European patent application no. 0 167 919 discloses benzodiazepine CCKand gastrin antagonists substituted in the 3-position by, inter alia, aphenyl urea and at the 5-position by, inter alia, a C₁₋₄ alkyl group.

Japanese patent application no. H3-223290 discloses thienodiazepineshaving inter alia a phenyl urea substituent and inter alia an aryl orheteroaryl substituent. The compounds are said to be CCK and/or gastrinantagonists.

The present invention provides thienodiazepine compounds of formula (I):##STR2## wherein:

R¹ represents H, C₁₋₆ alkyl optionally substituted by one or more halo,C₃₋₇ cycloalkyl, cyclopropylmethyl, CH₂ CO₂ R⁵ (where R⁵ is C₁₋₄ alkyl)or CH₂ CONR⁶ R⁷ (where R⁶ and R⁷ each independently represents H or C₁₋₄alkyl, or R⁶ and R⁷ together form a chain (CH₂)_(p) where p is 4 or 5);

R² represents a phenyl group optionally substituted by one or moresubstituents selected from C₁₋₆ alkyl, halo, hydroxy, C₁₋₄ alkoxy,(CH₂)_(q) -tetrazolyl optionally substituted in the tetrazole ring byC₁₋₄ alkyl, (CH₂)_(q) -imidazolyl, (CH₂)_(q) triazolyl (where q is 0, 1,2 or 3), 5-hydroxy-4-pyrone, NR⁶ R⁷, NR⁹ COR⁵, NR⁹ COR^(9') R⁵ (where R⁹and R^(9') are each independently H or C₁₋₄ alkyl), CONR⁶ R⁷ (where R⁶and R⁷ are as previously defined), SO(C₁₋₆ alkyl), SO₂ (C₁₋₆ alkyl),trifluoromethyl, CONHSO₂ R⁸, SO₂ NHCOR⁸ (where R⁸ is C₁₋₆ alkyl,optionally substituted aryl, 2,2-difluorocyclopropane ortrifluoromethyl), SO₂ NHR¹⁰ (where R¹⁰ is a nitrogen containingheterocycle), B(OH)₂, (CH₂)_(q) CO₂ H, where q is as previously defined;or

R² represents a group ##STR3## where W represents CH₂ or NR⁹, where R⁹is as previously defined and W¹ represents CH₂, or W and W¹ eachrepresent O;

R³ represents C₃₋₇ cycloalkyl optionally substituted by one or more C₁₋₄alkyl groups, or R³ is NR¹¹ R¹², where R¹¹ and R¹² each independentlyrepresent H; C₁₋₁₂ alkyl optionally substituted by NR⁹ R^(9') (where R⁹and R^(9') are as previously defined) or an azacyclic or azabicyclicgroup; C₄₋₉ cycloalkyl optionally substituted by one or more C₁₋₄ alkylgroups; C₄₋₉ cycloalkylC₁₋₄ alkyl optionally substituted in thecycloalkyl ring by one or more C₁₋₄ alkyl groups; optionally substitutedaryl; optionally substituted arylC₁₋₆ alkyl; or azacyclic or azabicyclicgroups; or R¹¹ and R¹² together form the residue of an optionallysubstituted azacyclic or azabicyclic ring system; and salts or prodrugsthereof.

It will be appreciated that formula (I) is intended to embrace allpossible isomers, including optical isomers, and mixtures thereof,including racemates.

As used herein, the definition of each expression, when it occurs morethan once in any structure, is intended to be independent of itsdefinition elsewhere in the same structure.

The present invention includes within its scope prodrugs of thecompounds of formula (I) above. In general, such prodrugs will befunctional derivatives of the compounds of formula (I) which are readilyconvertible in vivo into the required compound of formula (I).Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in "Design of Prodrugs"ed. H. Bungaard, Elsevier, 1985.

Halo includes fluoro, chloro, bromo and iodo. Preferably halo will befluoro or chloro.

As used herein, unless otherwise indicated, alkyl means straight orbranched chain saturated hydrocarbon.

As used herein, azacyclic means non-aromatic nitrogen-containingmonocyclic, and azabicyclic means non-aromatic nitrogen-containingbicyclic.

Unless otherwise stated, aryl means optionally substituted carbocyclicor heterocyclic aromatic groups, especially phenyl.

Heteroaryl means aromatic rings preferably having 5 or 6 ring atoms andcontaining at least one atom selected from O, S and N.

A subgroup of compounds according to the invention is represented bycompounds of formula (I) wherein R¹ represents C₁₋₆ alkyl, C₃₋₇cycloalkyl, cyclopropylmethyl, CH₂ CO₂ R⁵ or CH₂ CONR⁶ R⁷ ; R²represents a phenyl group optionally substituted by one or moresubstituents selected from C₁₋₆ alkyl, halo, hydroxy, C₁₋₄ alkoxy,(CH₂)_(q) -tetrazolyl optionally substituted in the tetrazole ring byC₁₋₄ alkyl, (CH₂)_(q) -imidazolyl, (CH₂)_(q) triazolyl (where q is 0, 1,2 or 3), 5-hydroxy-4-pyrone, NR⁶ R⁷, NR⁹ COR⁵, NR⁹ COR^(9') R⁵ (where R⁹and R^(9') are each independently H or C₁₋₄ alkyl) CONR⁶ R⁷ (where R⁶and R⁷ are as previously defined), SO(C₁₋₆ alkyl), SO₂ (C₁₋₆ alkyl),trifluoromethyl, CONHSO₂ R⁸, SO₂ NHCOR⁸ (where R⁸ is C₁₋₆ alkyl,optionally substituted aryl, 2,2-difluorocyclopropane ortrifluoromethyl), SO₂ NHR¹⁰ (where R¹⁰ is a nitrogen containingheterocycle), B(OH)₂, (CH₂)_(r) CO₂ H, where r is 0, 1 or 2; or

R² represents a group ##STR4## where W represents CH₂ or NR^(9;) and R³represents C₃₋₇ cycloalkyl or NR¹¹ R¹², where R¹¹ and R¹² eachindependently represent H, C₁₋₁₂ alkyl, C₄₋₉ cycloalkyl, optionallysubstituted aryl, optionally substituted arylC₁₋₆ alkyl or azacyclic orazabicyclic groups, or R¹¹ and R¹² together form the residue of anazacyclic or a bridged azabicyclic ring system; and pharmaceuticallyacceptable salts or prodrugs thereof.

When R¹ is C₃₋₇ cycloalkyl, suitable cycloalkyl groups includecyclopropyl, cyclopentyl and cyclohexyl groups, preferably cyclopropyl.

Preferably R¹ is C₁₋₆ alkyl optionally substituted by one or more halo,such as C₁₋₄ alkyl optionally substituted by 1, 2 or 3 fluoro. Preferredvalues for R¹ include, methyl, n-propyl and isobutyl. More preferably R¹is methyl or n-propyl.

Suitable values for R⁸ include methyl, ethyl, i-propyl, t-butyl, phenyland trifluoromethyl.

When R⁸ is optionally substituted aryl, this will preferably beoptionally substituted phenyl. Suitable substituents include C₁₋₄ alkyl,C₁₋₄ alkoxy, halo and trifluoromethyl. Preferred is unsubstituted phenylor phenyl substituted by C₁₋₆ alkyl, for example, phenyl substituted byC₁₋₆ alkyl in the ortho position.

When R⁸ is C₁₋₆ alkyl, it will preferably represent C₁₋₄ alkyl.Particularly preferred are methyl and iso-propyl, especially iso-propyl.

When R² is phenyl substituted by SO₂ NHR¹⁰, suitable values of R¹⁰include, for example, thiazole, thiadiazole and pyrazine.

Preferably q is zero.

Preferably R² is 5-indanyl or phenyl substituted by methyl.

When R² represents monosubstituted phenyl, the substituent willpreferably be located at the 3- or 4-position of the phenyl ring, morepreferably the 3position. When R² represents disubstituted phenyl, thesubstituents will preferably be located at the 3- and 4-positions. WhenR² represents a group ##STR5## the fused 5-membered ring will preferablybe fused across the 3 and 4 positions of the phenyl ring.

When R³ represents C₃₋₇ cycloalkyl optionally substituted by one or moreC₁₋₄ alkyl, it will preferably represent cyclopentyl, cyclohexyl orcycloheptyl, more preferably cyclohexyl, optionally substituted by oneor more methyl.

When R³ represents a group NR¹¹ R¹² where R¹¹ or R¹² representsoptionally subtituted aryl or optionally substituted arylC₁₋₆ alkyl,suitable aryl groups include phenyl, thienyl, furyl, pyrrolyl andpyridinyl, preferably phenyl. Suitable aryl substituents include, forexample, C₁₋₄ alkyl, C₁₋₄ alkoxy, halo and trifluoromethyl.

When R¹¹ or R¹² represents an azacyclic or azabicyclic group, or C₁₋₆alkyl substituted by azacyclic or azabicyclic group, the azacyclic orazabicyclic group may contain, in addition to the nitrogen atom, afurther heteroatom selected from O and S, or a group NR¹³ where R¹³ is Hor C₁₋₄ alkyl.

When R¹¹ or R¹² represents an azacyclic group or C₁₋₆ alkyl substitutedby an azacyclic group, the azacyclic group will suitably contain from 5to 10 ring atoms.

When R¹¹ or R¹² represents an azabicyclic group or C₁₋₆ alkylsubstituted by an azabicyclic group, the azabicyclic group will suitablycontain from 7 to 10 ring atoms.

When R¹¹ or R¹² represents C₄₋₉ cycloalkyl substituted by one or moreC₁₋₄ alkyl groups or C₄₋₉ cycloalkylC₁₋₄ alkyl substituted in thecycloalkyl ring by one or more C₁₋₄ alkyl groups, the C₁₋₄ alkyl groupsmay be located on any available ring carbon atom. In particular, geminaldisubstitution is provied for. The C₁₋₄ alkyl groups will preferably bemethyl groups.

Suitably R¹¹ and R¹² are selected from H, C₁₋₆ alkyl, such as methyl,ethyl and n-propyl, C₄₋₉ cycloalkyl, such as cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl, optionally substituted by one or more methylgroups, C₄₋₉ cycloalkylC₁₋₄ alkyl, such as cyclohexylmethyl, arylC₁₋₆alkyl, such as benzyl, C₁₋₆ alkyl substituted by NR⁹ R^(9') such as CH₂CH₂ N(CH₃)₂, C₁₋₆ alkyl substituted by an azacyclic group, such as C₁₋₄alkyl substituted by morpholinyl, and azacyclic groups, such asN-methylpiperidine.

When R¹¹ and R¹² together form the residue of an azacyclic orazabicyclic ring system, the azacyclic or azabicyclic ring system maycontain, in addition to the nitrogen atom to which R¹¹ and R¹² areattached, a second heteroatom selected from O, S or a group NR²² whereR²² is H, C₁₋₄ alkyl CO₂ R^(a), COR^(a) or SO₂ R^(a) where R^(a) is C₁₋₆alkyl, optionally substituted phenyl or benzyl optionally substituted inthe phenyl ring by one or more substituents, where the phenylsubstituents are selected from C₁₋₄ alkyl, C₁₋₄ alkoxy, halo andtrifluoromethyl.

When R¹¹ and R¹² together form the residue of an azacyclic ring system,the ring system may be substituted by one or more groups selected fromC₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, halo, trifluoromethyl, oxo, SR⁵, NR⁶R⁷, NR⁹ C₁₋₄ alkylR²³, ═NOR⁹ or ##STR6## where R⁶, R⁷, R⁹ and R⁵ are aspreviously defined, R²³ is halo or trifluoromethyl, and b is 2 or 3. Thesubstituents may be located on any available carbon atom. In particular,geminal disubstitution is provided for where appropriate. Particularlysuitable substituents include oxo, ketyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,trifluoromethyl and NHC₁₋₄ alkylCF₃ groups. Preferred are C₁₋₆ alkylgroups, especially methyl.

When R¹¹ and R¹² form the residue of an azacyclic ring system, the ringsystem suitably contains from 5 to 10 ring atoms, preferably 6, 7 or 8ring atoms, more preferably 7 ring atoms.

When R¹¹ and K¹² together form the residue of an azabicyclic ringsystem, the azabicyclic ring system may be fused, spiro or bridged,preferably fused or bridged, more preferably bridged. The azabicyclicring system may optionally be substituted by one or more C₁₋₄ alkyl,such as methyl, groups. The alkyl substituents may be located on anyavailable carbon atoms of the azabicyclic ring system. In particular,geminal disubstitution is provided for.

Preferably the azabicyclic ring system is unsubstituted.

Suitably the azabicyclic ring system contains from 7 to 10 ring atoms,preferably 7, 8 or 9 ring atoms.

Particularly preferred are compounds of formula (I) wherein R¹¹ and R¹²together form the residue of an azacyclic ring system substituted by oneor more methyl groups, or R¹¹ and R¹² together form the residue of abridged azabicyclic ring system, especially3-azabicyclo[3.2.2]nonan-3-yl.

Particularly preferred are compounds of formula (I) wherein R³represents C₅₋₇ cycloalkyl, especially cyclohexyl.

Preferably the salts of the compounds of formula (I) arepharmaceutically acceptable, but non-pharmaceutically acceptable saltsmay be used for the preparation of pharmaceutically acceptable salts.The pharmaceutically acceptable salts of the compounds of formula (I)include the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds from formula (I) formed, e.g., from non-toxicinorganic or organic acids or bases. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, nitric andthe like; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, steric, lactic, malic, tartaric, citric,ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulphanilic, 2-acetoxy benzoic, fumaric,toluenesulphonic, methanesulphonic, ethane disulphonic, oxalic andisothionic.

The salts of the present invention can be synthesized from the compoundof formula (I) which contain a basic or acidic moiety by conventionalchemical methods. Generally, the salts are prepared by reacting the freebase or acid with stoichiometric amounts or with an excess of thedesired salt-forming inorganic or organic acid or base in a suitablesolvent or various combinations of solvents.

The present invention also encompasses a pharmaceutical compositioncomprising a compound of formula (I), or a salt or prodrug thereof and apharmaceutically acceptable carrier or diluent.

The compounds of formula (I) and their salts and prodrugs, may beadministered to animals, preferably to mammals, and most especially to ahuman subject either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical compostion, according tostandard pharmaceutical practice. The compounds can be administeredorally, parenterally, including by intravenous, intramuscular,intraperitoneal or subcutaneous administration, or topically.

For oral use of an antagonist of CCK, according to this invention, theselected compounds may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavouring agents may be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

For topical administration, a compound of formula (I) may be formulatedas, for example, a suspension, lotion, cream or ointment.

For topical administration, pharmaceutically acceptable carriers are,for example, water, mixtures of water and water-miscible solvents suchas lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols,petroleum based jelly, ethyl cellulose, ethyl oleate,carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate andother conventionally-employed non-toxic, pharmaceutically acceptableorganic and inorganic carriers. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving,wetting agents, bodying agents and the like, as for example,polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500,4,000, 6,000 and 10,000, antibacterial components such as quaternaryammonium compounds, phenylmercuric salts known to have cold sterilizingproperties and which are non-injurious in use, thimerosal, methyl andpropyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredientssuch as sodium chloride, sodium borate, sodium acetates, gluconatebuffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetraacetic acid, and the like.

The compounds of formula (I) antagonise CCK and/or gastrin and areuseful for the treatment and prevention of disorders including centralnervous system disorders wherein CCK and/or gastrin may be involved.Examples of such disease states include gastrointestinal diseases,including gastrointestinal ulcers, such as peptic and duodenal ulcers,irritable bowel syndrome, gastroesophagenal reflux disease or excesspancreatic or gastrin secretion, acute pancreatitis, or motilitydisorders; central nervous system disorders, including central nervoussystem disorders caused by CCK interaction with dopamine, serotonin andother monoamine neurotransmitters, such as neuroleptic disorders,tardive dyskinesia, Parkinson's disease, psychosis or Gilles de laTourette syndrome; depression; schizophrenia; disorders of appetiteregulatory systems; Zollinger-Ellison syndrome, antral and cellhyperplasia, or pain.

The compounds of formula (I) are particularly useful in the treatment orprevention of neurological disorders involving anxiety disorders andpanic disorders, wherein CCK and/or gastrin is involved. Examples ofsuch disorders include panic disorders, anxiety disorders, panicsyndrome, anticipatory anxiety, phobic anxiety, panic anxiety, chronicanxiety and endogenous anxiety.

The compounds of formula (I) are also useful for directly inducinganalgesia, opiate or non-opiate mediated, as well as anesthesia or lossof the sensation of pain.

The compounds of formula (I) may further be useful for preventing ortreating the withdrawal response produced by chronic treatment or abuseof drugs or alcohol. Such drugs include, but are not limited tobenzodiazepines, cocaine, alcohol and nicotine.

The compounds of formula (I) may further by useful in the treatment ofstress and its relationship with drug abuse.

The compounds of formula (I) may further be useful in the treatment ofoncologic disorders wherein CCK may be involved. Examples of suchoncologic disorders include small cell adenocarcinomas and primarytumours of the central nervous system glial and neuronal cells. Examplesof such adenocarcinomas and tumours include, but are not limited to,tumours of the lower oesophagus, stomach, intestine, colon and lung,including small cell lung carcinoma.

The compounds of formula (I) may also be useful as neuroprotectiveagents, for example, in the treatment and/or prevention ofneurodengenerative disorders arising as a consequence of suchpathological conditions as stroke, hypoglycaemia, cerebral palsy,transient cerebral ischaemic attack, cerebral ischaemia during cardiacpulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy,Huntington's chorea, Alzheimer's disease, Amyotrophic Lateral Sclerosis,Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as fromdrowning, spinal cord and head injury, and poisoning by neurotoxins,including environmental neurotoxins.

The compounds of formula (I) may further be used to induce miosis fortherapeutic purposes after certain types of examination and intraocularsurgery. An example of intraocular surgery would include cateractsurgery with implantation of an artificial lens. The CCK antagonistcompounds of this invention can be used to prevent miosis occuring inassociation with iritis, ureitis and trauma.

The present invention therefore provides a compound of formula (I) or asalt or prodrug thereof for use in the preparation of a medicament.

The present invention also provides a compound of formula (I) for use intherapy.

In a further or alternative embodiment the present invention provides amethod for the treatment or prevention of a physiological disorderinvolving CCK and/or gastrin which method comprises administration to apatient in need thereof of a CCK and/or gastrin antagonising amount of acompound of formula (I).

When a compound according to formula (I) is used as an antagonist of CCKor gastrin in a human subject, the daily dosage will normally bedetermined by the prescibing physician with the dosage generally varyingaccording to the age, weight, and response of the individual patient, aswell as the severity of the patient's symptoms. However, in mostinstances, an effective daily dosage wll be in the range from about0.005mg/kg to about 100 mg/kg of body weight, and preferably, of from0.05 mg/kg to about 50 mg/kg, such as from about 0.5 mg/kg to about 20mg/kg of body weight, administered in single or divided doses. In somecases, however, it may be necessary to use dosages outside these limits.For example, animal experiments have indicated that doses as low as 1 ngmay be effective.

In effective treatment of panic syndrome, panic disorder, anxietydisorder and the like, preferably about 0.05 mg/kg to about 0.5 mg/kg ofCCK antagonist may be administered orally (p.o.), administered in singleor divided doses per day (b.i.d.). Other routes of administration arealso suitable.

For directly inducing analgesia, anaesthesia or loss of pain sensation,the effective dosage preferably ranges from about 100 ng/kg to about 1mg/kg by systemic administration. Oral administration is an alternativeroute, as well as others.

In the treatment or irritable bowel syndrome, preferably about 0.1 to 10mg/kg of CCK antagonist is administered orally (p.o.), administered insingle or divided doses per day (b.i.d.). Other routes of administrationare also suitable.

The use of a gastrin antagonist as a tumour palliative forgastrointestinal neoplasma with gastrin receptors, as a modulator ofcentral nervous activity, treatment of Zollinger-Ellison syndrome, or inthe treatment of peptic ulcer disease, an effective dosage of preferablyabout 0.1 to about 10 mg/kg administered one-to-four times daily isindicated.

For use as neuroprotective agents the effective dosage preferably rangesfrom about 0.5 mg/kg to about 20 mg/kg.

Because these compounds antagonise the function of CCK in animals, theymay also be used as feed additives to increase the food intake ofanimals in daily dosage of preferably about 0.05 mg/kg to about 50 mg/kgof body weight.

The compounds of formula (I) may be prepared from by reaction ofintermediates of formula (II) with compounds of formula (III) ##STR7##wherein R¹, R² and R³ are as defined for formula (I) above, one of R³⁰and R³¹ represents NH₂ and the other of R³⁰ and R³¹ represents --N═C═O.

The reaction is conveniently effected in a suitable organic solvent,such as an ether, for example, tetrahydrofuran.

Conveniently R³⁰ represents NH₂ and R³¹ represents --N═C═O.

Intermediates of formula (II) wherein R³⁰ represents --N═C═O(hereinafter intermediates (IIB)) may be prepared from the correspondingcompounds of formula (II) wherein R³⁰ is NH₂ (hereinafter intermediates(IIA)) by reaction with triphosgene in the presence of a base, such as atertiary amine, for example, triethylamine. The reaction is convenientlyeffected in a suitable organic solvent, such as an ether, for example,tetrahydrofuran, suitably at low temperature, such as about 0° C.Intermediates of formula (III) wherein R³¹ is --N═C═O (intermediates(IIIB)) may be prepared from the corresponding amines wherein R³¹ is NH₂(intermediates (IIIA)) analogously.

Intermediates of formula (IIA) may be prepared from compounds of formula(IV): ##STR8## wherein R¹ and R³ are as defined for formula (I) above,by reduction, for example, by catalytic hydrogenation or reduction usinga suitable metal under acidic conditions.

Suitable hydrogenation catalysts include, for example, nobel metalcatalysts, e.g. ruthenium, or rhodium which may be supported, forexample, on carbon.

The reaction is preferably conducted in a suitable organic solvent, suchas an alcohol, for example, methanol, at elevated temperature, e.g.about 60° C.

Suitable reduction methods using metals include, for example, the use ofzinc and trifluoroacetic acid in a suitable solvent, such as aceticacid, preferably at elevated temperature, e.g. at about 40° C.

Intermediates of formula (IV) may be prepared from compounds of formula(V) ##STR9## wherein R¹ and R³ are as defined for formula (I), byreaction with isoamyl nitrite in the presence of a base.

Suitable bases of use in the reaction include alkali metal alkoxides,such as potassium t-butoxide.

Compounds of formula (V) wherein R³ is NR¹¹ R¹² may be prepared fromcompounds of formula (VI) ##STR10## wherein R¹ is as defined for formula(I) and Hal represents halo, such as chloro, by reaction with an amineof formula HNR¹¹ R¹².

Compounds of formula (V) wherein R³ is cycloalkyl may be prepared fromcompounds of formula (VII) ##STR11## wherein R³ is C₃₋₇ cycloalkyl, by areaction sequence comprising:

(i) reaction with a compound of formula Hal-COCH₂ -Hal, wherein Halrepresents halo, such as chloro or bromo, in the presence of a base,such as an organic base, for example pyridine. The reaction isconveniently effected in a suitable organic solvent, such as an ether,for example, diethyl ether.

(ii) Treatment with ammonia, conveniently in a suitable organic solvent,such as an alcohol, for example, methanol.

Compounds of formula (VII) may be prepared by reaction of intermediatesof formula (VIII) with the compound of formula (IX) ##STR12## wherein R³is C₃₋₇ cycloalkyl, in the presence of a base.

Suitable bases of use in the reaction include tertiary amines, forexample, triethylamine.

The reaction is conveniently effected in a suitable organic solvent,such as an alcohol, for example, methanol.

Intermediates of formula (VIII) may be prepared from commerciallyavailble compounds of formula R³ CO₂ R¹⁸ (wherein R³ is C₃₋₇ cycloalkyland R¹⁸ is alkyl) by treatment with butyl lithium and acetonitrile. Thereaction is conveniently effected in a suitable organic solvent, such asan ether, for example, tetrahydrofuran, at low temperature, such asabout -78° C.

The compound of formula (IX) is commerically available.

Intermediates of formulae (II), (IV) and (V) are novel compounds andform a further aspect of the present invention.

The present invention therefore provides intermediates of formula (A):##STR13## wherein R¹ and R³ are as defined for formula (I) and R²⁰represents H, NOH, --N═C═O or NH₂.

Where the above-described process for the preparation of the compoundsaccording to the invention gives rise to mixtures of stereoisomers theseisomers may, if desired, be separated, suitably by conventionaltechniques such as preparative chromatography.

The novel compounds may be prepared in racemic form, or individualenantiomers may be prepared either by enantiospecific synthesis or byresolution. The novel compounds may, for example, be resolved into theircomponent enantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (-)-di-p-toluoyl-L-tartaric acid and/or(+)-di-p-toluoyl-D-tartaric acid followed by fractional crystallizationand regeneration of the free base. The novel compounds may also beresolved by formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, enantiomers of the novel compounds may be separated byHPLC using a chiral column.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following examples are provided to assist in a further understandingof the invention. Particular materials employed, species and conditionsare intended to be further illustrative of the invention and notlimitative of the scope thereof.

EXAMPLE 1N-[3(R,S)-5-cyclohexyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-thienodiazepine-3-yl]-N'-(3-methylphenyl)urea

a) 2-Amino-3-cyclohexanoyl-thiophene

To a solution butyl lithium (160 ml of a 2.5 mol solution in hexane) intetrahydrofuran (280 ml) at -780° C. was added acetonitrile (10.88 ml)over 15 mins. After stirring at -780° C. for 1 h, methylcyclohexanecarboxylate (28.6 ml) was added dropwise over 15 mins. After2h at -78° C., the reaction mixture was allowed to warm to roomtemperature and stirred for a further 1 h. Water (500 ml) was added tothe mixture which was then washed with diethyl ether (2×500 ml). Theaqueous solution was acidified to pill with concentrated hydrochloricacid and extracted with diethyl ether (2×500 ml). The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuo to give anoil (28.2 g). This was dissolved in methanol (50 ml) with2,5-dihydroxydithiane (14.22 g) and triethylamine (16 ml) was addeddropwise. The reaction mixture was stirred overnight and the requiredproduct was collected by filtration (26.6 g): M.P. 148°-152° C., NMR δ(CDCl₃) 1.15-1.80 (10H, m), 2.79 (1H, m), 6.06 (1H, d, J=5.8 H_(z)),6.71 (2H, br, s, NH₂), 6.90 (1H, d, J=5.8 H_(z)); MS (CI) m/e 210 [MH]⁺.

b) 5-Cyclohexyl-2,3-dihydro-2-oxo-1,4-thienodiazenine

The product from step a) (26.6 g) was dissolved in diethyl ether (500ml) with pyridine (10.17 ml) and bromoacetyl bromide (13.4 ml) was addeddropwise at room temperature. When the addition was complete, thereaction mixture was stirred for 1 h at ambient temperature, then washedwith water (2×200 ml), brine (1×200 ml), dried (Na₂ SO₄), filtered andconcentrated in vacuo. The residue was dissolved in methanol (600 ml)which had been presaturated with ammonia gas (200 ml) at -40° C. Thesolution was allowed to warm to room temperature and stirred for 14 h.The solvent was evaporated under vacuum and the residue was partitionedbetween dichloromethane (500 ml) and water (300 ml). The organic layerwas washed with brine (1×200 ml), dried (Na₂ SO₄), filtered andconcentrated under vacuum. The residue was purified by chromatography onsilica gel using hexane to 50% ethyl acetate in hexane as eluent to givethe required product (4 g): MP 248° C. dec; NMR δ (DMSO) 1.16-1.71 (10H,m), 2.69 (1H, m), 3.99 (2H, s), 7.16 (2H, m), 11.07 (1H, br, s, NH); MS(CI) m/e 249 [MH]⁺.

c) 5-Cyclohexyl-2,3-dihydro-1-methyl-2-oxo-1,4-thienodiazepine

The product from step b) (2.66 g) was dissolved in toluene (150 ml),heated to reflux and dimethyl formamide-dimethyl acetal (7.12 ml) wasadded dropwise. After heating under reflux for 1 h, the reaction mixturewas allowed to cool and concentrated under vacuum. The residue waspurified by silica gel chromatography (using 20% ethyl acetate in hexaneto 50% ethyl acetate in hexane as eluent) to give the required product(2.8 g) NMR (CDCl₃) 1.16-1.81 (10H, m), 2.59 (1H, m), 3.43 (3H, s), 4.21(2H, s), 7.00 (2H, s); MS (CI) m/e 263 [MH]⁺.

d) 5-Cyclohexyl-1-methyl-3-hydroxyimino-2-oxo-1,4-thienodiazepine

The product from the previous reaction (3.33 g) was dissolved in toluene(100 ml), cooled to -20° C. and potassium tertiary butoxide (3.33 g) wasadded. After 20 minutes, isoamylnitrite (1.99 ml) was added and thereaction mixture was stirred at -20° C. in the dark for 18 h. 1 NHydrochloric acid was added to quench the reaction and the mixture waspartitioned between water (200 ml) and ethyl acetate (2×250 ml). Thecombined organic layers were dried (MgSO₄), filtered and concentratedunder vacuum. The residue was purified by silica gel chromatographyusing 30-50% ethyl acetate in hexane as eluent to give the requiredproduct (1.1 g) NMR (CDCl₃) 1.89-1.96 (10H, m), 2.76 (1H, m), 3.53 (3H,s) 7.01 (2H, m), 7.96 (1H, br, s); MS (CI) m/e 292 [MH]⁺.

e)N-[3(R,S)-5-Cyclohexyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-thienodiazepin-3-yl]-N'-(3-methylphenyl)urea

The product from step d) (0.3 g) was dissolved in methanol (40 ml) andheated at 60° C. under 50 p.s.i. of hydrogen in the presence of 10%Rhodium on carbon catalyst (0.3 g) for 6h. The reaction mixture wasfiltered and concentrated under vacuum. The residue was dissolved intetrahydrofuran (30 ml) and meta tolylisocyanate (0.133 ml) was added.The reaction mixture was stirred at room temperature for 14h thenconcentrated under vacuum. The residue was purified using 20-30% ethylacetate in hexane as eluent to give a product which was recrystallisedusing diethyl ether/petrol 60-80 to give the title compound (41 mg): MP190° C. (sub); NMR (DMSO) 1.02-1.99 (10H, m), 2.23 (3H, s), 2.74 (1H,m), 3.40 (3H, s) 5.11 (1H, d, J=8.4 Hz), 6.73 (1H, d, J=8.4 Hz),7.08-7.46 (6H, m), 8.86 (1H, s); MS (CI) m/e 411 [MH]⁺ ; Found C, 64.44;H, 6.51; N, 13.66. C₂₂ H₂₆ N₄ O₂ S requires C, 64.36; H, 6.38; N,13.65%.

EXAMPLE 2A

    ______________________________________                                        Tablets containing 1-25 mg of compound                                                       Amount mg                                                      Compound of formula (I)                                                                        1.0       2.0    25.0                                        ______________________________________                                        Microcrystalline cellulose                                                                     20.0      20.0   20.0                                        Modified food corn starch                                                                      20.0      20.0   20.0                                        Lactose          58.5      57.5   34.5                                        Magnesium Stearate                                                                              0.5       0.5    0.5                                        ______________________________________                                    

EXAMPLE 2B

    ______________________________________                                        Tablets containing 26-100 mg of compound                                                     Amount mg                                                      Compound of formula (I)                                                                        26.0      50.0    100.0                                      ______________________________________                                        Microcrystalline cellulose                                                                     80.0      80.0     80.0                                      Modified food corn starch                                                                      80.0      80.0     80.0                                      Lactose          213.5     189.5   139.5                                      Magnesium Stearate                                                                              0.5       0.5     0.5                                       ______________________________________                                    

The compound of formula (I), cellulose, lactose and a portion of thecorn starch are mixed and granulated with 10% corn starch paste. Theresulting granulation is sieved, dried and blended with the remainder ofthe corn starch and the magnesium stearate. The resulting granulation isthen compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0mg, 50.0 mg and 100 mg of the active compound per tablet.

EXAMPLE 3

    ______________________________________                                        Parenteral injection                                                                             Amount mg                                                  Compound of formula (I)                                                                          1 to 100                                                   ______________________________________                                        Citric Acid Monohydrate                                                                          0.75                                                       Sodium Phosphate   4.5                                                        Sodium Chloride    9                                                          Water for Injections                                                                             to 1 ml                                                    ______________________________________                                    

The sodium phosphate, citric acid monohydrate and sodium chloride aredissolved in a portion of the water. The compound of formula (I) isdissolved or suspended in the solution and made up to volume.

EXAMPLE 4

    ______________________________________                                        Topical formulation                                                                                  Amount mg                                              Compound of formula (I)                                                                              1-10                                                   ______________________________________                                        Emulsifying Wax        30                                                     Liquid paraffin        20                                                     White Soft Paraffin    to 100                                                 ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. Thecompound of formula (I) is added and stirring continued until dispersed.The mixture is then cooled until solid.

BIOLOGICAL ACTIVITY

The CCK-A and CCK-B antagonising activity of the compounds describedherein was evaluated using the assays described in published Europeanpatent application no. 0514133. The method essentially involvesdetermining the concentration of the test compound required to displace50% of the specific ¹²⁵ I-CCK from rat pancreas (CCK-A) or guinea pigbrain (CCK-B). The data in Table 1 were obtained for the compound ofExample 1.

                  TABLE I                                                         ______________________________________                                        CCK RECEPTOR BINDING RESULTS                                                  IC.sub.50 (nM)                                                                Compound       .sup.125 I-CCK                                                                         .sup.125 I-CCK                                        of Ex #        Pancreas Brain                                                 ______________________________________                                        1              6.7      46                                                    ______________________________________                                    

We claim:
 1. A compound of Formula (I) or a pharmaceutically acceptablesalt thereof: ##STR14## wherein: R¹ represents H, C₁₋₆ alkyl optionallysubstituted by one or more halo, C₃₋₇ cycloalkyl, cyclopropylmethyl, CH₂CO₂ R⁵ (where R⁵ is C₁₋₄ alkyl) or CH₂ CONR⁶ R⁷ (where R⁶ and R⁷ eachindependently represents H or C₁₋₄ alkyl, or R⁶ and R⁷ together form achain (CH₂)_(p) where p is 4 or 5);R² represents a phenyl groupoptionally substituted by one or more substituents selected from C₁₋₆alkyl, halo, hydroxy, C₁₋₄ alkoxy, (CH₂)_(q) -tetrazolyl optionallysubstituted in the tetrazole ring by C₁₋₄ alkyl, (CH₂)_(q) -imidazolyl,(CH₂)_(q) triazolyl (where q is 0, 1, 2 or 3), 5-hydroxy-4-pyrone, NR⁶R⁷, NR⁹ COR⁵, NR⁹ COR^(9') R⁵ (where R⁹ and R^(9') are eachindependently H or C₁₋₄ alkyl), CONR⁶ R⁷ (where R⁶ and R⁷ are aspreviously defined), SO(C₁₋₆ alkyl), SO₂ (C₁₋₆ alkyl), trifluoromethyl,CONHSO₂ R⁸, SO₂ NHCOR⁸ (where R⁸ is C₁₋₆ alkyl, optionally substitutedaryl being phenyl optionally substituted by a substitutent selected fromthe group consisting of: C₁₋₄ alkyl, C₁₋₄ alkoxy, halo andtrifluoromethyl; 2,2-difluorocyclopropane or trifluoromethyl), SO₂ NHR¹⁰(where R¹⁰ is a nitrogen containing heterocycle selected from the groupconsisting of: thiazole, thiadiazole, and pyrazino), B(OH)₂, (CH₂)_(q)CO₂ H, where q is as previously defined; or R² represents a group##STR15## where W represents CH₂ or NR⁹, where R⁹ is as previouslydefined and W¹ represents CH₂, or W and W¹ each represent O; and R³represents C₃₋₇ cycloalkyl optionally substituted by one or more C₁₋₄alkyl groups, or R³ is NR¹¹ R¹², where R¹¹ and R¹² each independentlyrepresent H; C₁₋₁₂ alkyl optionally substituted by NR⁹ R^(9') (where R⁹and R^(9') are as previously defined) or an azacyclic selected frommorpholinyl and piperidinyl or azabicyclic group selected from3-aza-bicyclo[3.2.2]nonan-3-yl; C₄₋₉ cycloalkyl optionally substitutedby one or more C₁₋₄ alkyl groups; C₄₋₉ cycloalkylC₁₋₄ alkyl optionallysubstituted in the cycloalkyl ring by one or more C₁₋₄ alkyl groups;optionally substituted aryl which is selected from the group consistingof: phenyl, thienyl, furyl, pyrrolyl and pyridyl, which can besubstituted with a group selected from the group consisting of: C₁₋₄alkyl, C₁₋₄ alkoxyl, halo and trifluoromethyl; optionally substitutedarylC₁₋₆ alkyl wherein optionally substituted aryl is definedimmediately prior; or azacyclic or azabicyclic groups as defined above;or R¹¹ and R¹² together form the residue of an optionally substitutedazacyclic or azabicyclic ring system selected from3-azabicyclo[3.2.2]nonan-3-yl.
 2. A compound as claimed in claim 1wherein R¹ represents C₁₋₆ alkyl, C₃₋₇ cycloalkyl, cyclopropylmethyl,CH₂ CO₂ R⁵ or CH₂ CONR⁶ R⁷ ; R² represents a phenyl group optionallysubstituted by one or more substituents selected from C₁₋₆ alkyl, halo,hydroxy, C₁₋₄ alkoxy, (CH₂)_(q) -tetrazolyl optionally substituted inthe tetrazole ring by C₁₋₄ alkyl, (CH2)_(q) imidazolyl, (CH₂)_(q)triazolyl (where q is 0, 1, 2 or 3), 5-hydroxy-4-pyrone, NR⁶ R⁷, NR⁹COR⁵, NR⁹ COR9'R⁵ (where R⁹ and R^(9') are each independently H or C₁₋₄alkyl) CONR⁶ R⁷ (where R⁶ and R⁷ are as previously defined), SO(C₁₋₆alkyl), SO₂ (C₁₋₆ alkyl), trifluoromethyl, CONHSO₂ R⁸, SO₂ NHCOR⁸ (whereR⁸ is C₁₋₆ alkyl, optionally substituted aryl as defined above in claim1, 2,2-difluorocyclopropane or trifluoromethyl), SO₂ NHR¹⁰ (where R¹⁰ isa nitrogen containing heterocycle as defined above in claim 1), B(OH)₂,(CH₂)_(r) CO₂ H, where r is 0, 1 or 2; orR² represents a group ##STR16##where W represents CH₂ or NR^(9;) and R³ represents C₃₋₇ cycloalkyl orNR¹¹ R¹², where R¹¹ and R¹² each independently represent H, C₁₋₁₂ alkyl,C₄₋₉ cycloalkyl, optionally substituted aryl as defined above in claim1, optionally substituted arylC₁₋₆ alkyl as defined above in claim 1 orazacyclic or azabicyclic groups as defined above in claim 1, or R¹¹ andR¹² together form the residue of an azacyclic or a bridged azabicyclicring system as defined above in claim 1; or pharmaceutically acceptablesalts thereof.
 3. A compound as claimed in claim 1 wherein R¹ is C₁₋₆alkyl.
 4. A compound as claimed in claim 1 wherein R¹ is C₁₋₆ alkylsubstituted by one or more halo.
 5. A compound as claimed in claim 1wherein R² represents 5-indanyl or phenyl substituted by methyl.
 6. Acompound as claimed in claim 1 wherein R³ represents NR¹¹ R¹² and R¹¹and R¹² together form the residue of an azacyclic ring system as definedabove in claim 1 substituted by one or more methyl groups, or R¹¹ andR¹² together form the residue of a bridged azabicyclic ring system asdefined above in claim
 1. 7. A compound as claimed in claim 1 wherein R³represents C₅₋₇ cycloalkyl.
 8. A compound as claimed in claim 1 selectedfromN-[3(R,S)-5-cyclohexyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-thienodiazepine-3yl-]-N'-(3-methylphenyl)urea;or pharmaceutically acceptable salts thereof.
 9. A pharmaceuticalcomposition comprising a compound as claimed in claim 1 in associationwith a pharmaceutically acceptable carrier.